Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (lymphangiomyomas and angiomyolipomas). The disease, which presents in middle-aged women, is characterized by the proliferation of abnormal smooth muscle containing premelanosomal structures similar to those found in melanoma cells. A clinical protocol has enabled the Branch to assemble a large cohort of patients with LAM and to document the natural history of the disease, the histopathological findings, the radiographic appearance, characteristic pulmonary function abnormalities, and the association with an inherited disorder, tuberous sclerosis complex. Gene expression and cell regulatory pathways have been examined in tissue samples. Lung diffusion (DLCO) and/or forced expiratory volume in the first second (FEV1) are decreased, but, frequently, not in parallel with each other. Since cardiopulmonary exercise testing (CPET) provides information that is not obtainable from resting cardiopulmonary tests, we performed CPET in 217 LAM patients and correlated exercise data with clinical markers of severity, CT scans, lung function, and histology. Maximal oxygen uptake (VO2 max) was decreased in 162 patients, of whom 28 did not reach anaerobic threshold (AT); 29 had low oxygen uptake at AT and 54 developed hypoxemia. Hypoxemia occurred even in patients with near normal DLCO and FEV1. VO2 max decreased with increasing score of histological LAM severity and was correlated with CT scans, use of oxygen, and resting PaO2. DLCO and FEV1, however, were the only significant predictors of VO2 max. We conclude that CPET uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements in patients with LAM.